Introduction

Glaucoma is a chronic neurodegenerative eye disease marked by death of retinal ganglion cells (RGCs) and progressive visual field loss despite controlled intraocular pressure (IOP). Recent research highlights that RGCs have extraordinarily high metabolic demands (long unmyelinated axons, constant spiking) and sit at a “metabolic precipice,” making them vulnerable to age-related energy deficits and mitochondrial dysfunction (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). A key metabolic change in aging retinas is depletion of NAD⁺ (nicotinamide adenine dinucleotide), an essential coenzyme in mitochondrial energy production. Age-dependent NAD⁺ decline is documented in glaucoma models and is thought to render RGCs susceptible to “metabolic crisis” under stress (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Accordingly, nicotinamide (NAM, the amide form of vitamin B3) and other NAD⁺ boosters have emerged as candidate neuroprotectants. NAM is a precursor in the NAD⁺ salvage pathway, and boosting NAD⁺ can enhance mitochondrial function, activate longevity enzymes, and buffer metabolic stress. Preclinical studies in glaucoma models and early clinical trials have begun to investigate whether NAD⁺ repletion can improve RGC resilience and slow vision loss (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This article reviews the evidence from animal models and human studies, explains the proposed mechanisms (mitochondrial support, sirtuin activation, metabolic buffering) in the context of longevity biology, and discusses trial designs, outcomes, dosing, safety, adherence, and open questions about long-term use of NAM and other NAD⁺ boosters in glaucoma.

NAD⁺ Metabolism in Retinal Ganglion Cells

NAD⁺ is a ubiquitous coenzyme that facilitates ATP production via glycolysis and oxidative phosphorylation, and serves as a substrate for enzymes that regulate cell survival (sirtuins), DNA repair (PARPs), and stress responses (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In RGCs – among the most energy-demanding neurons – NAD⁺ levels are critical for maintaining mitochondrial health and redox balance. In glaucoma models (DBA/2J mice), retinal NAD⁺ declines significantly with age, correlating with early mitochondrial dysfunction and vulnerability to IOP stress (pmc.ncbi.nlm.nih.gov). Bansal et al. showed that age-dependent NAD⁺ loss in DBA/2J RGCs “renders [them] vulnerable to a metabolic crisis following periods of high IOP” (pmc.ncbi.nlm.nih.gov). Similarly, human data suggest that metabolic dysregulation, including NAD⁺ depletion, contributes to glaucomatous neurodegeneration. Chiu et al. note that NAD⁺ depletion is a key feature of RGC stress and that nicotinamide supplementation—by replenishing NAD⁺—could counteract this “progressive depletion” and preserve mitochondrial function (pmc.ncbi.nlm.nih.gov).

Nicotinamide is converted to NAD⁺ via the salvage pathway (NAM → NMN → NAD⁺), involving enzymes like NAMPT and NMNAT. Aging and stress can impair these enzymes, leading to an NAD⁺ deficit (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). NAD⁺ boosters also include nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which enter the same pathway. By elevating NAD⁺, these precursors support cellular bioenergetics and enable sirtuin (SIRT) activity, which normally helps sustain mitochondrial integrity and stress resistance (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In glaucomatous RGCs, key NAD⁺-producing enzymes are downregulated and NAD⁺consumption (via PARP1) is upregulated, leading to energy failure (pmc.ncbi.nlm.nih.gov). Boosting NAD⁺ supply can reverse these deficits, maintaining SIRT1/SIRT3 function and preventing NAD⁺ collapse (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

In summary, the NAD⁺-centered view of glaucoma frames it as a metabolic optic neuropathy: RGC survival depends on robust NAD⁺-driven metabolism, which declines with age. Therefore, NAD⁺ restoration via nicotinamide or other precursors is a rational strategy to bolster RGC energy homeostasis and neuroprotection (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Preclinical Evidence for Nicotinamide Neuroprotection

A growing body of preclinical research supports nicotinamide as a potent RGC neuroprotectant in glaucoma models. Williams et al. (2017) found that dietary NAM dramatically prevented glaucoma in DBA/2J mice: at a high dose, 93% of eyes in treated mice showed no glaucomatous RGC loss (versus much higher loss in controls), equating to a ~10-fold reduction in glaucoma risk (pmc.ncbi.nlm.nih.gov). Notably, NAM had no effect on IOP in these mice, indicating that its benefit was purely neuroprotective (pmc.ncbi.nlm.nih.gov). Histology confirmed NAM prevented optic nerve cupping and axon loss (pmc.ncbi.nlm.nih.gov). In ex vivo models, NAM rescued RGCs from axotomy-induced degeneration, preserving soma size, dendritic complexity, and axonal integrity in cultured retina (pmc.ncbi.nlm.nih.gov).

Complementing genetic models, induced hypertension models in rodents also demonstrate NAM’s efficacy. In rat ocular hypertension (OHT) experiments, NAM supplementation dose-dependently prevented RGC death and shrinkage. Tribble et al. (2021) showed that OHT rats fed NAM had significantly less RGC loss than untreated OHT, with higher doses (human-equivalent ~8 g/day) providing robust protection (pmc.ncbi.nlm.nih.gov). NAM also preserved RGC dendritic morphology and axon caliber under stress (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Parallel studies in inducible glaucoma and axotomy models found similar results: NAM increased RGC survival across somas, axons, and dendrites against multiple insults (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Metabolomics revealed that OHT induces widespread retinal and optic nerve metabolic disruption which NAM largely prevented (pmc.ncbi.nlm.nih.gov). Mechanistic studies showed NAM increased retinal ATP production and mitochondrial density while dampening excess neuronal firing (pmc.ncbi.nlm.nih.gov).

Other NAD⁺ precursors and related interventions have shown benefit, supporting the NAD⁺ hypothesis. Overexpression of the NAD-producing enzyme NMNAT1 or use of the Wld^s genetic variant (which stabilizes NMNAT activity) cooperated with NAM to block glaucoma progression in mice (pmc.ncbi.nlm.nih.gov). Nicotinamide riboside (NR) has also protected RGC axons in optic nerve injury models via SIRT1-dependent mechanisms. For instance, NR conferred resistance to TNF-induced optic neuropathy through a SIRT1–autophagy pathway (pmc.ncbi.nlm.nih.gov) (demonstrating NAD precursor → SIRT1 activation → RGC protection). Together, these data indicate that bolstering NAD⁺ metabolism preserves mitochondrial function and blunts cell stress in RGCs, making them far more resilient to glaucomatous injury.

Mechanisms: Mitochondrial Support, Sirtuin Activation, and Metabolic Stress Buffering

Mitochondrial Support: Boosting NAD⁺ directly fuels mitochondrial respiration. NAD⁺ is the electron acceptor for dehydrogenase reactions in glycolysis and the TCA cycle. In NAD-depleted RGCs, mitochondria become fragmented, small, and energetically impaired. NAM repletion reverses these changes: experimental studies found that NAM increases oxidative phosphorylation capacity and ATP availability. In OHT models, NAM-treated retinas showed higher oxygen consumption rates and larger, more motile mitochondria (pmc.ncbi.nlm.nih.gov). These enhancements allow RGCs to meet energy demands and resist oxidative damage. By supporting mitochondrial health, NAM keeps RGC neurons above the “metabolic precipice” reported by Bhartiya (pmc.ncbi.nlm.nih.gov).

Sirtuin Activation: NAD⁺ is an obligate cofactor for the sirtuin class of deacetylases (notably SIRT1 and SIRT3) that mediate adaptive stress responses and longevity pathways. Under normal conditions, SIRT1 deacetylates key transcription factors and enzymes to drive antioxidant defenses and mitochondrial biogenesis. In glaucoma, however, NAD⁺ deficiency hinders SIRT1/3 activity even if expression is upregulated (pmc.ncbi.nlm.nih.gov). NAM supplementation replenishes NAD⁺ and reactivates sirtuins. For example, in optic nerve crush models, overexpression or activation of SIRT1 (e.g. by resveratrol or NAD⁺ boost) reduced RGC oxidative stress and improved survival (pmc.ncbi.nlm.nih.gov). In mouse glaucoma models, the protection afforded by NAM was absent in SIRT1 knockout eyes, underscoring the enzyme’s role in NAD-related neuroprotection (pmc.ncbi.nlm.nih.gov). Thus, NAD⁺ precursors may exert part of their effect by enabling sirtuin-driven preservation of mitochondrial integrity and DNA repair in RGCs.

Metabolic Stress Buffering: Nicotinamide and NAD⁺ help cells cope with acute metabolic stress (e.g. episodes of high IOP or ischemia). NAD⁺ acts as an electron sink and detoxifier of free radicals, blunting metabolic disturbances. Tribble et al. reported that NAM “buffers and prevents metabolic stress” in glaucomatous retina (pmc.ncbi.nlm.nih.gov). By keeping NAD⁺ pools sufficient, NAM ensures steady ATP production even under stress, preventing the energy collapse that leads to cell death. Notably, NAM-treated RGCs showed lower resting firing rates (pmc.ncbi.nlm.nih.gov), which conserves energy under duress. In DBA/2J mice, age-driven NAD⁺ decline was linked to a “metabolic crisis” upon IOP elevation (pmc.ncbi.nlm.nih.gov); NAM prevented this crisis, maintaining normal metabolic profiles. In short, NAD⁺ repletion gives RGCs a metabolic “reserve”, reducing vulnerability to glaucomatous insults.

These mechanisms tie directly into longevity biology. NAD⁺-dependent pathways (like sirtuins) are key anti-aging regulators. NAD⁺ levels fall in many tissues with age, and raising them is a strategy shown to improve healthspan. For example, long-term nicotinamide supplementation in mice improved metabolic health (better glucose control, less fatty liver and inflammation) though without extending maximum lifespan (pmc.ncbi.nlm.nih.gov). Similarly, chronic NMN treatment delayed age-related decline and even increased median lifespan by ~8–9% in female mice (pubmed.ncbi.nlm.nih.gov). These studies highlight how NAD⁺ boosters enhance resilience to stress and inflammation, hallmarks of aging. In the eye, preserving NAD⁺ aligns with this by maintaining RGC vitality as part of “healthy aging” of the visual system.

Emerging Clinical Evidence in Glaucoma

Clinical research on NAD⁺ boosters in glaucoma is still nascent but growing. Several small trials have tested oral nicotinamide (with or without other metabolic agents) in glaucoma patients, using functional and structural endpoints. A phase II randomized trial by De Moraes et al. combined high-dose nicotinamide (up to 3,000 mg/day) with sodium pyruvate (3,000 mg/day) in treated open-angle glaucoma patients (pmc.ncbi.nlm.nih.gov). After a 3-week escalation to the target dose, the NAM+pyruvate group showed a significantly greater number of improving visual field locations compared to placebo (median of 12 vs 5 improved points; P<0.01) (pmc.ncbi.nlm.nih.gov). This suggests short-term enhanced function of RGCs, although the study was too brief to assess true progression. Importantly, the combination was well-tolerated: only mild gastrointestinal symptoms occurred, and no serious adverse events were seen (pmc.ncbi.nlm.nih.gov).

Another ongoing study is testing nicotinamide riboside (NR) in glaucoma. Leung et al. have initiated a double-blind trial (NCT0XXXXX) where participants receive 300 mg/day of NR or placebo for 24 months (pmc.ncbi.nlm.nih.gov). The primary endpoint is the rate of RNFL thinning on OCT, with secondary outcomes including time to visual field progression, RNFL/GCL thinning (trend analysis), and change in visual field sensitivity (pmc.ncbi.nlm.nih.gov). Such structural and functional endpoints are standard in neuroprotection trials. Notably, Leung’s group chose optical coherence tomography (OCT) – especially average RNFL and ganglion cell complex (GCC) thickness – as the main outcome (pmc.ncbi.nlm.nih.gov). This reflects the goal of preserving RGC axons, detectable as slowed thinning on OCT. Other endpoints in these and similar trials include pattern electroretinogram (PERG) or photopic negative response (PhNR) – objective measures of inner retinal/RGC function – and standard automated perimetry (SAP) visual fields. For instance, one early small study (Hui et al., 2020) used PhNR amplitude as the primary measure of NAM’s effect (pmc.ncbi.nlm.nih.gov). These choices illustrate the trend: structural (OCT) and functional (ERG, field) markers are all being evaluated as ways to capture neuroprotective benefit.

Beyond these, very preliminary human data hint at vascular effects. Gustavsson et al. reported that two months of 1 g/day nicotinamide in glaucoma patients led to small but significant increases in retinal capillary density on OCT-angiography (pmc.ncbi.nlm.nih.gov). In parallel rat studies, NAM prevented the retinal vascular dropout usually seen in ocular hypertension. These findings suggest that NAD⁺ boosters might also improve ocular perfusion or microcirculation as part of neuroprotection.

In summary, early trials indicate nicotinamide is safe (apart from known mild side effects) and can improve or stabilize visual function measures in the short term (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Larger and longer studies are now underway. A particularly ambitious trial (NCT06991712, registered in Hong Kong) is comparing four NAD⁺ precursors (NR, NAM, NMN, and niacin) versus placebo in moderate glaucoma, using short-term visual field sensitivity as the endpoint (pmc.ncbi.nlm.nih.gov). Such studies will help define which precursor and dose is optimal.

Study Endpoints and Design Considerations

Clinical trials of glaucoma neuroprotection typically include both structural endpoints and functional endpoints. Structural measures rely on imaging the retinal nerve fiber layer (RNFL) or ganglion cell complex (GCC) with OCT. Slowed thinning of RNFL/GCC is interpreted as slowed axon loss. For example, the NR trial cited above uses the rate of RNFL change over 24 months as the primary outcome (pmc.ncbi.nlm.nih.gov). Other trials evaluate “progression” by event-based algorithms: e.g. time to confirmed visual field progression or RNFL thinning beyond test-retest variability (pmc.ncbi.nlm.nih.gov).

Functional endpoints assess RGC performance. The pattern electroretinogram (PERG) – or its small-flash counterpart PhNR – is sensitive to RGC dysfunction even before cell death. Early clinical studies of NAM have used PhNR amplitudes to gauge neuroenhancement (pmc.ncbi.nlm.nih.gov). Visual field testing (24-2 SAP) remains the gold-standard functional endpoint. Clinical trials often count the number of visual field test locations that improve or deteriorate beyond noise levels. In De Moraes et al.’s trial, the outcome was the increase in “improving” locations on 24-2 fields after supplementation (pmc.ncbi.nlm.nih.gov). Others may use standard perimetry progression rates (dB/year) or survival analyses of progression events.

Study design considerations include patient selection, dosing, and duration. So far, trials have enrolled stable glaucoma patients (often under effective IOP therapy) with residual visual loss. This minimizes confounding by acute IOP changes and focuses on long-term neurodegeneration. Dosing of NAM in studies has been high. In preclinical rodent work, doses from 200 to 800 mg/kg were effective – roughly equivalent to 2–8 g/day in a 60-kg human (pmc.ncbi.nlm.nih.gov). Clinical trials have used up to 3 grams per day. The NAM+pyruvate trial escalated from 1 g to 3 g per day of NAM (pmc.ncbi.nlm.nih.gov). The NR trial uses 300 mg/day of NR (pmc.ncbi.nlm.nih.gov), reflecting NR’s higher bioavailability and the fact that lower doses raise NAD⁺ effectively. For context, nicotinic acid (niacin) is often used at 2–3 g/day for lipid disorders; nicotinamide lacks the flushing effect, allowing similar doses without cutaneous side effects.

Patients in these studies must continue their standard IOP-lowering therapy, as NAD boosters do not significantly lower IOP themselves. In fact, high-dose NAM in mice had no effect on pressure while protecting RGCs (pmc.ncbi.nlm.nih.gov). (An interesting note: at extremely high NAM intake (~9.8 g/day equivalent), DBA/2J mice had slightly less IOP elevation than untreated, though this effect is marginal (pmc.ncbi.nlm.nih.gov). No meaningful IOP reduction is expected in humans at safe doses.) By design, neuroprotection trials typically randomize subjects to NAD-enhancing therapy or placebo, while keeping IOP care constant.

Safety, Adherence, and Interactions

Nicotinamide is generally well tolerated, but high-dose use raises safety questions. At standard vitamin doses (≈0.5–1 g/day), NAM has an excellent safety profile. Chronic use of 1.5–3 g/day in clinical trials produced only mild gastrointestinal discomfort (nausea, diarrhea) and fatigue in a minority of patients (pmc.ncbi.nlm.nih.gov). Unlike nicotinic acid (which causes flushing via prostaglandins), nicotinamide causes no flush. No serious systemic adverse events were observed in short-term glaucoma trials (pmc.ncbi.nlm.nih.gov). However, very high doses have potential risks. A case report described drug-induced liver injury in a glaucoma trial participant taking 3 g/day NAM (pubmed.ncbi.nlm.nih.gov) – reminding us that hepatotoxicity is possible. This risk is not surprising since early studies noted headache, dizziness and vomiting in some individuals given ~6 g at once (pmc.ncbi.nlm.nih.gov). Animal studies suggest lower NAD doses are likely safer. Nicotinamide riboside at 300 mg/day (far below toxicity thresholds) is expected to be very safe (pmc.ncbi.nlm.nih.gov).

Long-term safety remains an open question. Chronic high NAM can alter methylation metabolism and, in theory, may affect DNA repair enzymes (PARPs) or methyl-donor pools (pmc.ncbi.nlm.nih.gov). On the flip side, no increase in cancer or major metabolic issues has been observed in available studies. Importantly, investigators have explicitly called for caution and monitoring in ongoing trials due to these unknowns (pmc.ncbi.nlm.nih.gov). Liver function tests should be followed when using 2–3 g/day for months.

Adherence is another practical concern. Taking several large pills daily can be burdensome, especially for older patients on multiple medications. Splitting the NAM dose into 2–3 times per day can improve tolerability and compliance. Nicotinamide riboside has a much lower prescribed dose (e.g. 1–2 capsules of 150 mg), which may aid adherence. Importantly, NAD+ boosters are often available as dietary supplements; patients might self-prescribe them. Physicians should guide patients on appropriate dosing and monitor for interactions. Fortunately, no clinically significant drug–drug interactions with common glaucoma medications (e.g. prostaglandins, beta-blockers, or carbonic anhydrase inhibitors) are known. If anything, NAD boosters could complement standard therapy: they target neuroprotection rather than IOP, so they add to pressure-lowering treatment without interference.

Longevity Biology and Aging Context

The interest in NAD+ boosters for glaucoma sits within a broader trend in aging biology. NAD+ decline is a hallmark of aging in many tissues, and NAD+ repletion has been linked to improved healthspan. In mice on high-fat diet, long-term nicotinamide improved metabolic parameters (glucose homeostasis, reduced fatty liver and inflammation) though it did not extend lifespan (pmc.ncbi.nlm.nih.gov). Another study found that lifelong nicotinamide riboside maintained youthful gene expression and delayed frailty; notably, female mice receiving NMN had an ~8.5% increase in median lifespan (pubmed.ncbi.nlm.nih.gov). These studies imply that NAD+ restoration supports healthy aging by enhancing resistance to stress and inflammation.

By analogy, neuropreservation in glaucoma may be seen as part of retinal “healthy aging.” The same pathways that protect against age-related systemic decline – improving mitochondrial resiliency, activating sirtuins, reducing oxidative stress – also help RGCs survive glaucomatous injury. Glaucoma often manifests in the elderly, so any intervention that bolsters longevity pathways could have dual benefits for general health and vision. It is noteworthy that late-life NAD+ boosters have shown benefits in multiple organ systems without requiring life-long administration; glaucoma trials only need to show a functional or structural effect over a period of years. Still, the glaucoma field must grapple with the question: Will chronic supplementation for years (even decades) remain safe and effective? Lessons from longevity trials (e.g., about optimal dosing, periodic vs. continuous use, and biomarkers of NAD+ levels) will inform long-term glaucoma strategies.

Conclusion

Emerging evidence from laboratory and early human studies suggests that nicotinamide and other NAD⁺ boosting strategies can bolster retinal ganglion cell resilience in glaucoma. By reinforcing mitochondrial energy production, reactivating protective sirtuin enzymes, and buffering metabolic stress, NAD⁺ replenishment protects RGC soma, axons and dendrites in animal glaucoma models (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), and improves visual function measures in small clinical trials (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Clinical endpoints of interest include OCT RNFL/GCC thinning, PERG/PhNR amplitudes, and visual field sensitivity. So far, high-dose nicotinamide (1–3 g/day) appears generally safe aside from mild GI effects, though rare liver toxicity has been reported (pubmed.ncbi.nlm.nih.gov). Nicotinamide riboside at ~300 mg/d is even better tolerated. The main uncertainties are long-term safety and adherence over years, precise dose–response in humans, and how NAD⁺ therapies interact with standard IOP-lowering treatments. Nevertheless, the biology strongly justifies continued trials: glaucoma is increasingly seen as a metabolic neurodegeneration, and NAD⁺ boosting targets fundamental aging processes shared by RGCs. Future large-scale, multi-year trials will determine whether NAD⁺ boosters can truly slow vision loss in glaucoma patients.

TAGS: ["Glaucoma","Nicotinamide","NAD+","Neuroprotection","Retinal Ganglion Cells","Mitochondria","Sirtuins","Visual Field","OCT","Longevity"]